AB0718 LEVELS OF PHOSPHO-STAT3 ASSOCIATE WITH TREATMENT DURATION IN GIANT CELL ARTERITIS
Authors: I. Esen, M. Sandovici, P. Heeringa, A. Boots, E. Brouwer, Y. Van Sleen, W. Abdulahad
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Giant Cell Arteritis (GCA) is a granulomatous inflammation of medium and large arteries, that occurs in elderly individuals. Evidence on the immunopathology of GCA indicates that the IL-6 IL-23 Th17 axis is one of the dominant pathways and the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) acts downstream of this axis. Targeted IL-6 receptor blockade by tocilizumab (TCZ) emerges as a promising treatment option. However, there is no further data on which patients would benefit most. The therapeutic effect of TCZ in a substantial group of GCA patients suggests that the vasculitis is driven by the JAK/STAT pathway in these patients. <h3>Objectives</h3> To investigate whether phosphorylated STAT (pSTAT) signatures in GCA patients can aid the stratification of patients for personalized treatment in GCA. <h3>Methods</h3> To investigate the expression of pSTAT, a phosphoflow method combined with a fluorescent cell barcoding technique (FCB) was developed. Frozen peripheral mononuclear cells (PBMCs) from treatment-naive GCA patients (n=18), infection controls (INF, n=11) and age-matched healthy controls (HC, n=15) were included in this study. PBMCs were incubated with IL-6 for 30 minutes. Cells were stained for T-cell markers (CD3, CD4, CD8, CD19, CD45RO) and STAT signature markers (pSTAT1, pSTAT3, pSTAT5). Serum IL-6 levels were measured by Luminex assay. The baseline inflammation markers and pSTAT3 in prospectively followed GCA patients was assessed by Kaplan-Meier curves for prognostic analysis. The pSTAT3 activity after treatment was evaluated in paired baseline, 3 months and 1-year samples. <h3>Results</h3> After IL-6 stimulation, we found a lowered proportion of pSTAT3 in CD4+ memory T-cells of GCA patients and INF controls compared to HCs. In GCA patients, proportion of pSTAT3 in CD4+ memory T cells was negatively associated with ESR at diagnosis (p=0.001, r=-0.729). Considering the link between IL-6 and ESR, we stratified GCA patients according to high (&gt;1.5pg/mL) and low (≤1.5pg/mL) serum IL-6 levels and found that that the decrease in pSTAT3 in CD4+ memory T cells was especially found in GCA patients with high serum IL-6 levels. Importantly, we found that GCA patients with low ESR and high pSTAT3 at the time of diagnosis significantly predicted long-term glucocorticoid requirement. Levels of pSTAT3 in patients with high serum IL-6 levels at diagnosis normalized after 1 year of treatment. <h3>Conclusion</h3> We demonstrate a relation between serum IL-6 levels and in vitro pSTAT3 expression in GCA. Importantly, our results suggest that pSTAT3 can be an important prognostic marker in GCA. <h3>Disclosure of Interests</h3> Idil Esen: None declared, Maria Sandovici: None declared, Peter Heeringa: None declared, Annemieke Boots: None declared, Elisabeth Brouwer Consultant of: speaker/consulting fees from Roche, Yannick van Sleen: None declared, Wayel Abdulahad: None declared.